Radiation necrosis occurs in 5-25% of patients who undergo stereotactic radiosurgery (SRS) for brain metastases. Intravoxel incoherent motion (IVIM) uses MRI diffusion-weighted imaging (DWI) to assess regional perfusion. We investigated the utility of IVIM to differentiate recurrent tumor from radionecrosis after SRS. Patients who had SRS and subsequent surgical resection of what was thought to be either tumor progression or necrosis were included. ROIs were contoured on the pre-operative post-Gd T1-weighted images and transferred to DWI images using automated co-registration. The perfusion fraction (f) was calculated using asymptotic fitting and the mean f (fmean), 90th percentile for f (f90), mean ADC (ADCmean) and 10th percentile for ADC (ADC10) were calculated. Pathology reports were used to identify the predominant feature (necrosis versus tumor). Nine patients with ten lesions were included. One lesion exhibited pure necrosis while the other nine were mixed; three were predominantly (>75%) tumor, three predominantly necrosis, and three were equal parts of both. The perfusion fraction was significantly higher in cases with predominantly tumor compared to those with predominantly necrosis (fmean 0.10±0.01 vs 0.08±0.01, p=0.02 and f90 0.22±0.01 vs 0.14±0.02, p<0.001). ADC did not differentiate tumor from necrosis (ADCmean 0.97±0.23 vs 1.02±0.36, p=0.8 and ADC10 0.53±0.29 vs 0.76±0.29, p=0.33). The IVIM perfusion fraction is useful in differentiating recurrent tumor from radionecrosis in brain metastases treated with SRS. This is the first study to evaluate IVIM against the gold standard (histopathology).

Background: The therapeutic value of second-generation anticonvulsants such as lamotrigine has not been clearly established in neonates and infants with seizures. To address this issue, we assessed the efficacy of lamotrigine for treating neonatal and infantile seizures, detailed the dosing regimens used, and described its tolerability and safety profile. Methods: This retrospective study included patients (age 0-12 months) diagnosed with seizures and treated with lamotrigine, as monotherapy or adjunctive therapy, by pediatric neurologists at Centre mère-enfant Soleil du CHUQ from 2004 to 2014. The frequency of seizures and EEG patterns were compared before and after introduction of lamotrigine during the first months of life. Data on initial and maintenance doses, rate and magnitude of dosing increments, and adverse effects were collected. Results: Treatment with lamotrigine was initiated in 32 neonates and 13 infants. At first follow-up (mean duration 3 months), 76 % (n = 34) showed a significant (≥50%) reduction of seizures and 64% (n= 29) improvement of EEG pattern compared to baseline. The efficacy in monotherapy and adjunctive therapy was similar. A single case of cutaneous hypersensitivity reaction requiring cessation of treatment was reported. Conclusions: This study suggests that lamotrigine is a useful, safe, and well-tolerated anticonvulsant alternative for the treatment of seizures in neonates and infants.

Background: Understanding the epidemiology of traumatic brain injury (TBI) is essential to shape public health policy, implement prevention strategies, and justify allocation of resources toward research, education, and rehabilitation in TBI. There is not, to our knowledge, a systematic review of population-based studies addressing the epidemiology of TBI that includes all subtypes. We performed a comprehensive systematic review and meta-analysis of the worldwide incidence of TBI. Methods: A search was conducted on May 23, 2014, in Medline and EMBASE according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Abstracts were screened independently and in duplicate to identify original research. Study quality and ascertainment bias were assessed in duplicate using a previously published tool. Demographic data and incidence estimates from each study were recorded, along with stratification by age, gender, year of data collection, and severity. Results: The search strategy yielded 4944 citations. Two hundred and sixteen articles met criteria for full-text review; 144 were excluded. Hand searching resulted in ten additional articles. Eighty-two studies met all eligibility criteria. The pooled annual incidence proportion for all ages was 295 per 100,000 (95% confidence interval: 274-317). The pooled incidence rate for all ages was 349 (95% confidence interval: 96.2-1266) per 100,000 person-years. Incidence proportion and incidence rate were examined to see if associated with age, sex, country, or severity. Conclusions: We conclude that most TBIs are mild and most TBIs occur in males among the adult population. The incidence of TBI varies widely by ages and between countries. Despite being an important medical, economic, and social problem, the global epidemiology of TBI is still not well-characterized in the current literature. Understanding the incidence of TBI, particularly mild TBI, remains challenging because of nonstandardized reporting among neuroepidemiological studies.

Background: The StatNet electrode set is a system that can be applied by a non-electroencephalogram (EEG) technologist after minimal training. The primary objectives of this study are to assess the quality and reliability of the StatNet recordings in comparison to the conventional EEG. Methods: Over 10 months, 19 patients with suspected nonconvulsive status epilepticus were included from university hospital emergency settings. Each patient received a StatNet EEG by a trained epilepsy fellow and a conventional EEG by registered technologists. We compared the studies in a blinded fashion, for the timeframe from EEG order to the setup time, start of acquisition, amount of artifact, and detection of abnormalities. The nonparametric Mann-Whitney two-sample t test was used for comparisons. The kappa score was used to assess reliability. Results: Mean age of patients was 61±16.3 (25-93) years. The inter-observer agreement for detection of abnormal findings was 0.83 for StatNet and 0.75 for conventional EEG. Nonconvulsive status epilepticus was detected in 10% (2/19) in both studies. The delay from the time of EEG requisition to acquisition was shorter in the StatNet (22.4±2.5 minutes) than the conventional EEG (217.7±44.6 minutes; p<0.0001). The setup time was also shorter in the StatNet (9.9±0.8 minutes) compared with the conventional EEG (17.8±0.8 minutes; p<0.0001). There was no difference in the percentage of artifact duration between the two studies (p=0.89). Conclusion: This study demonstrates that StatNet EEG is a practical and reliable tool in the emergency setting, which reduces the delay of testing compared with conventional EEG, without significant compromise of study quality.

Recently, many cases of autoimmune limbic encephalitis with positive GAD65 (glutamic acid decarboxylase) antibodies have been described in the scientific literature. However, it remains an understudied topic of great relevance to practicing neurologists. Thus, we report here a review of published cases, in English, of autoimmune limbic encephalitis with this type of antibodies, focusing on presenting symptoms and signs, associated conditions, and findings upon investigation. We also report treatment responses. We aim to offer a better description of the clinical spectrum of autoimmune limbic encephalitis associated with GAD65 antibodies as well as to expose its paraclinical features and outcome.

Cerebral vasospasm is a prolonged but reversible narrowing of cerebral arteries beginning days after subarachnoid hemorrhage. Progression to cerebral ischemia is tied mostly to vasospasm severity, and its pathogenesis lies in artery encasement by blood clot, although the complex interactions between hematoma and surrounding structures are not fully understood. The delayed onset of vasospasm provides a potential opportunity for its prevention. It is disappointing that recent randomized, controlled trials did not demonstrate that the endothelin antagonist clazosentan, the cholesterol-lowering agent simvastatin, and the vasodilator magnesium sulfate improve patient outcome. Minimizing ischemia by avoiding inadequate blood volume and pressure, administering the calcium antagonist nimodipine, and intervention with balloon angioplasty, when necessary, constitutes current best management. Over the past two decades, our ability to manage vasospasm has led to a significant decline in patient morbidity and mortality from vasospasm, yet it still remains an important determinant of outcome after aneurysm rupture.

Background: For optimal stroke prevention, best practices guidelines recommend carotid endarterectomy (CEA) for symptomatic patients within two weeks; however, 2013 Ontario data indicated that only 9% of eligible patients from outpatient Stroke Prevention Clinics (SPCs) achieved this target. The goal of our study was to identify modifiable system factors that could enhance the quality and timeliness of care among patients needing urgent CEA. Methods: We conducted a retrospective chart review of transient ischemic attack/stroke patients assessed in Champlain Local Health Integrated Network SPCs between 2011 and 2014 who subsequently underwent CEA. Descriptive statistics were used to define patient characteristics, timelines from symptom onset to CEA, and system factors that contributed to delays or improvements in care. Multivariate analysis was used to determine statistically significant variations between groups. Results: Seventy-five records were eligible for study inclusion. Median time from initial symptoms to CEA was 31 days, with 21.3% of patients undergoing surgery within 2 weeks. Significant delays were common in patient presentation and assessment following symptom onset, wait times for vascular imaging and neurological assessment, and time from surgical assessment to CEA completion. Rapid testing and triage, coupled with collaborative initiatives among SPC, surgical, and radiology teams were associated with significantly improved timelines. Conclusions: Success factors for rapid CEA are multifaceted, including system changes that address public awareness of stroke and 911 response, improvements in vascular imaging access, and redesign of clinical services to promote collaboration and fast-tracking of care. Implementation of performance measures to monitor and guide clinical innovations is recommended.

Objectives: Differentiating genetic myopathies from inflammatory myopathies can be challenging because of multiple overlapping clinical features. Examples are presented to highlight important clinical features that assist in the differentiation between the two. Methods: Clinical features including age at onset, history, pattern of weakness, serum creatine kinase activity, electromyography findings, and muscle biopsies are reported in six patients initially thought to have an inflammatory myopathy in whom the final diagnosis was a genetic myopathy. Results: All six patients met Bohan and Peter criteria for at least probable idiopathic polymyositis and were subsequently found to have a genetic myopathy (4 DYSF, RYR1, and GNE). The key distinguishing clinical were minimal to no response to immunosuppression and atypical involvement of distal muscles in the majority of cases. Conclusions: Patients diagnosed with inflammatory myopathies should be reevaluated for the possibility of a genetic myopathy if they fail to respond to a course of disease-modifying agents and/or there is atypical distal muscle involvement.

Multiple sclerosis is a chronic demyelinating disease characterized by focal and diffuse inflammation of the central nervous system resulting in significant physical and cognitive disabilities. Disease-modifying therapies targeting the dysfunctional immune response are most effective in the first few years after disease onset, indicating that there is a limited time window for therapy to influence the disease course. No evidence of disease activity is emerging as a new standard for treatment response and may be associated with improved long-term disability outcomes. An aggressive management strategy, including earlier use of more potent immunomodulatory agents and close monitoring of the clinical and radiologic response to treatment, is recommended to minimize early brain volume loss and slow the progression of physical and cognitive impairments in patients with relapsing-remitting multiple sclerosis.

Glioblastoma Multiforme (GBM) is the most common malignant primary brain neoplasm having a mean survival time of <24 months. This figure remains constant, despite significant progress in medical research and treatment. The lack of an efficient anti-tumor immune response and the micro-invasive nature of the glioma malignant cells have been explained by a multitude of immune-suppressive mechanisms, proven in different models. These immune-resistant capabilities of the tumor result in a complex interplay this tumor shares with the immune system. We present a short review on the immunology of GBM, discussing the different unique pathological and molecular features of GBM, current treatment modalities, the principles of cancer immunotherapy and the link between GBM and melanoma. Current knowledge on immunological features of GBM, as well as immunotherapy past and current clinical trials, is discussed in an attempt to broadly present the complex and formidable challenges posed by GBM.

Background: Ataluren is the first drug to treat the underlying cause of nmDMD. Methods: Phase 2 and 3 studies of ataluren in nmDMD were reviewed, with efficacy and safety/tolerability findings summarized. Results: Ataluren nmDMD trials include: a Phase 2a proof-of-concept study (N=38); a Phase 2b randomized controlled trial (RCT) (N=174); an ongoing US-based open-label safety extension study (N=108); an ongoing non-US-based open-label safety/efficacy extension study (N=94); and a Phase 3 RCT, ACT DMD (N=228), whose primary endpoint was change in six-minute walk distance (6MWD) over 48 weeks. The proof-of-concept study demonstrated increased dystrophin production in post-treatment muscle biopsies from ataluren-treated patients with nmDMD. The Phase 2b results demonstrated an ataluren treatment effect in 6MWD, timed function tests, and other measures of physical functioning, The Phase 3 ACT DMD results demonstrated an ataluren treatment effect in patients with nmDMD in both primary and secondary endpoints, particularly in those with a baseline 6MWD of 300-400m. Ataluren was consistently well-tolerated in all three trials, as well as in the ongoing extension studies. Trial findings will be presented in detail. Conclusions: The totality of the results demonstrates that ataluren enables nonsense mutation readthrough in the dystrophin mRNA, producing functional dystrophin and slowing disease progression.

Supported by: PTC Therapeutics Inc.

Background: Parkinson disease (PD) presents with motor and non-motor symptoms (NMS). The NMS often precede the onset of motor symptoms, but may progress throughout the disease course. Tremor dominant, postural instability gait difficulty (PIGD), and indeterminate phenotypes can be distinguished using Unified PD Rating scales (UPDRS-III). We hypothesized that the PIGD phenotype would be more likely to develop NMS, and that the non-dopamine–responsive axial signs would correlate with NMS severity. Methods: We conducted a retrospective cross-sectional chart review to assess the relationship between NMS and PD motor phenotypes. PD patients were administered the NMS Questionnaire, the UPDRS-III, and the Mini-Mental State Examination score. The relationship between NMS burden and PD subtypes was examined using linear regression models. The prevalence of each NMS among difference PD motor subtypes was analyzed using chi-square test. Results: PD patients with more advanced disease based on their UPDRS-III had higher NMS Questionnaire scores. The axial component of UPDRS-III correlated with higher NMS. There was no correlation between NMS and tremor scores. There was a significant correlation between PIGD score and higher NMS burden. PIGD group had higher prevalence in most NMS domains when compared with tremor dominant and indeterminate groups independent of disease duration and severity. Conclusions: NMS profile and severity vary according to motor phenotype. We conclude that in the PD population, patients with a PIGD phenotype who have more axial involvement, associated with advanced disease and poor motor response, have a higher risk for a higher NMS burden.

Background: Sensory ganglionopathy (SG) is characterised by asymmetrical sensory fibre degeneration, with the primary pathology occurring at the level of the dorsal root ganglion. It is seen in the context of autoimmune, paraneoplastic, and degenerative disorders. There is limited literature examining the electrophysiological correlate of the trigeminal ganglion and associated pathways, the blink reflex (BR), in cases of SG. Previous work has suggested that the BR is preserved in cases of SG associated with paraneoplasia. Methods: The local clinical neurophysiology database was searched for patients diagnosed with SG from peripheral nerve conduction studies in whom the BR was performed. Twenty-six patients were included in the final analysis. Results: Sjögren’s syndrome constituted the most common SG aetiology (8/26), followed by idiopathic cases (7/26) and paraneoplasia (5/26). BR abnormalities were seen in 9 of the 26 patients (34.6%) across all aetiologies. No patients reported sensory disturbance in the distribution of the trigeminal nerve, indicating that the changes noted are subclinical. Three patients showed abnormality of the R1 response; in the remaining six patients, only R2 responses were affected. Conclusions: Subclinical abnormalities of both R1 and R2 can be seen in the context of SG of varying aetiologies, including paraneoplasia. Performing the BR in patients with suspected of having SG may be helpful in providing additional evidence of patchy sensory fibre involvement that is characteristic of the disease.

Objective: The phrenic nerve and the contralateral seventh cervical (C7) nerve root are the most commonly used donor nerves in the treatment of total brachial plexus avulsion. The aim of this study was to determine if the phrenic nerve or the contralateral C7 nerve root yields a superior outcome for nerve transfer. Methods: A total of 60 Sprague-Dawley rats were randomly assigned to 1 of 3 groups. In Group A the phrenic nerve was used as the donor nerve; in Group B the contralateral C7 nerve root nerve was used as the donor nerve; in Group C the nerve was directly sutured. The results of behavioral assessment, electrophysiology, histology, nerve fiber count and muscle weight at 24 weeks postoperatively were recorded. Results: Group A showed a faster recovery time compared to Group B; however Group B showed a better functional recovery at the final outcome assessment compared to Group A. Conclusion: The contralateral C7 nerve root was better as the donor nerve for nerve transfer in the treatment of total brachial plexus avulsion.

Background Recent studies have strongly indicated the benefits of endovascular therapy for acute ischemic stroke, but what remains a continued debate is the role for general anaesthesia versus conscious sedation (CS) for such procedures. Retrospective studies have found poorer neurological outcomes in patients who underwent general anesthesia (GA); however, some have revealed worse baseline stroke severity in these patients.Methods This study is a retrospective cohort study aimed at comparing mortality and morbidity of GA versus CS in patients treated with endovascular intervention in acute ischemic stroke. Chi-square and t-test analyses were used. Results Patients in the GA (n=42) group were more likely to be deceased than those in the CS (n=67) group at hospital discharge, 3 months, and 6 months poststroke onset. Morbidity, as defined by modified Rankin Score, was significantly greater in the GA group at hospital discharge, and a similar trend was seen in morbidity at 3 months postdischarge. Conclusion General anesthesia for endovascular intervention in acute ischemic stroke was associated with increased mortality and poorer neurological incomes compared with conscious sedation. In our study, age, gender, history of hypertension, history of diabetes, and baseline National Institute of Health Stroke Scale were not significantly different between the groups. Although the need for a randomized, prospective study on this topic is clear, our study represents further corroboration of the safety and efficacy of conscious sedation in these procedures.

Brain tumours represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant pediatric brain tumour. Current molecular Nsubgroups of MB recognize distinct disease entities of which activated Wnt signaling (monosomy 6, exon 3 mutations in CTNNB1, and Wnt gene signature) is associated with a distinct subgroup and the best overall outcome. In contrast, only non-Wnt MBs are characterized by metastatic disease, increased rate of recurrence, and poor overall survivorship. Given the excellent clinical outcome in patients with Wnt-driven MB, we aimed to convert treatment-resistant MB subgroups into an ostensibly benign tumour through selective targeting by small molecule Wnt agonists (Wnt3A), GSK3 inhibitors (CHIR99021), and transgenic lines containing a stabilized beta-catenin mutant. Activated Wnt signaling resulted in decreased in vitro self-renewal and promoted differentiation within primary human MB stem cells. The clinical relevance of these findings were demonstrated with an in vivo survival advantage in mice containing orthotopic injections of cells containing a stabilized beta-catenin mutant representative of constitutively active Wnt signaling. Xenografts generated from Wnt-activated tumours were much smaller in size, maintained a much lower rate of proliferation, and reduction in key MB stem cell self-renewal genes (Bmi1, Sox2, Msi1, FoxG1). Our work establishes activated Wnt signaling as a novel treatment paradigm in childhood MB, while providing evidence for the context-specific tumour suppressive function of the canonical Wnt pathway.